Nature structural & molecular biology最新文献_第6页

Structural basis of the mechanism and inhibition of a human ceramide synthase 人类神经酰胺合成酶的机制和抑制作用的结构基础

Nature structural & molecular biology Pub Date : 2024-11-11 DOI: 10.1038/s41594-024-01414-3

Tomas C. Pascoa, Ashley C. W. Pike, Christofer S. Tautermann, Gamma Chi, Michael Traub, Andrew Quigley, Rod Chalk, Saša Štefanić, Sven Thamm, Alexander Pautsch, Elisabeth P. Carpenter, Gisela Schnapp, David B. Sauer

{"title":"Structural basis of the mechanism and inhibition of a human ceramide synthase","authors":"Tomas C. Pascoa, Ashley C. W. Pike, Christofer S. Tautermann, Gamma Chi, Michael Traub, Andrew Quigley, Rod Chalk, Saša Štefanić, Sven Thamm, Alexander Pautsch, Elisabeth P. Carpenter, Gisela Schnapp, David B. Sauer","doi":"10.1038/s41594-024-01414-3","DOIUrl":"https://doi.org/10.1038/s41594-024-01414-3","url":null,"abstract":"Ceramides are bioactive sphingolipids crucial for regulating cellular metabolism. Ceramides and dihydroceramides are synthesized by six ceramide synthase (CerS) enzymes, each with specificity for different acyl-CoA substrates. Ceramide with a 16-carbon acyl chain (C16 ceramide) has been implicated in obesity, insulin resistance and liver disease and the C16 ceramide-synthesizing CerS6 is regarded as an attractive drug target for obesity-associated disease. Despite their importance, the molecular mechanism underlying ceramide synthesis by CerS enzymes remains poorly understood. Here we report cryo-electron microscopy structures of human CerS6, capturing covalent intermediate and product-bound states. These structures, along with biochemical characterization, reveal that CerS catalysis proceeds through a ping-pong reaction mechanism involving a covalent acyl–enzyme intermediate. Notably, the product-bound structure was obtained upon reaction with the mycotoxin fumonisin B1, yielding insights into its inhibition of CerS. These results provide a framework for understanding CerS function, selectivity and inhibition and open routes for future drug discovery.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"13 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142598312","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Mechanism for Vipp1 spiral formation, ring biogenesis, and membrane repair Vipp1 螺旋形成、环状生物生成和膜修复的机制

Nature structural & molecular biology Pub Date : 2024-11-11 DOI: 10.1038/s41594-024-01401-8

Souvik Naskar, Andrea Merino, Javier Espadas, Jayanti Singh, Aurelien Roux, Adai Colom, Harry H. Low

引用次数: 0

Cryo-electron tomography reveals how COPII assembles on cargo-containing membranes 低温电子断层扫描揭示 COPII 如何在含货物的膜上组装

Nature structural & molecular biology Pub Date : 2024-11-07 DOI: 10.1038/s41594-024-01413-4

Euan Pyle, Elizabeth A. Miller, Giulia Zanetti

引用次数: 0

Tubulin acetyltransferases access and modify the microtubule luminal K40 residue through anchors in taxane-binding pockets 微管蛋白乙酰转移酶通过锚定在类黄酮结合袋中来获取和修改微管管腔内的 K40 残基

Nature structural & molecular biology Pub Date : 2024-11-04 DOI: 10.1038/s41594-024-01406-3

Jingyi Luo, Wai Hei Lam, Daqi Yu, Victor C. Chao, Marc Nicholas Zopfi, Chen Jing Khoo, Chang Zhao, Shan Yan, Zheng Liu, Xiang David Li, Chaogu Zheng, Yuanliang Zhai, Shih-Chieh Ti

{"title":"Tubulin acetyltransferases access and modify the microtubule luminal K40 residue through anchors in taxane-binding pockets","authors":"Jingyi Luo, Wai Hei Lam, Daqi Yu, Victor C. Chao, Marc Nicholas Zopfi, Chen Jing Khoo, Chang Zhao, Shan Yan, Zheng Liu, Xiang David Li, Chaogu Zheng, Yuanliang Zhai, Shih-Chieh Ti","doi":"10.1038/s41594-024-01406-3","DOIUrl":"https://doi.org/10.1038/s41594-024-01406-3","url":null,"abstract":"Acetylation at α-tubulin K40 is the sole post-translational modification preferred to occur inside the lumen of hollow cylindrical microtubules. However, how tubulin acetyltransferases access the luminal K40 in micrometer-long microtubules remains unknown. Here, we use cryo-electron microscopy and single-molecule reconstitution assays to reveal the enzymatic mechanism for tubulin acetyltransferases to modify K40 in the lumen. One tubulin acetyltransferase spans across the luminal lattice, with the catalytic core docking onto two α-tubulins and the enzyme’s C-terminal domain occupying the taxane-binding pockets of two β-tubulins. The luminal accessibility and enzyme processivity of tubulin acetyltransferases are inhibited by paclitaxel, a microtubule-stabilizing chemotherapeutic agent. Characterizations using recombinant tubulins mimicking preacetylated and postacetylated K40 show the crosstalk between microtubule acetylation states and the cofactor acetyl-CoA in enzyme turnover. Our findings provide crucial insights into the conserved multivalent interactions involving α- and β-tubulins to acetylate the confined microtubule lumen.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"241 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142574465","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel 异构 TRPC1/TRPC4 通道的冷冻电镜结构

Nature structural & molecular biology Pub Date : 2024-10-30 DOI: 10.1038/s41594-024-01408-1

Jongdae Won, Jinhyeong Kim, Jinsung Kim, Juyeon Ko, Christine Haewon Park, Byeongseok Jeong, Sang-Eun Lee, Hyeongseop Jeong, Sun-Hong Kim, Hyunwoo Park, Insuk So, Hyung Ho Lee

{"title":"Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel","authors":"Jongdae Won, Jinhyeong Kim, Jinsung Kim, Juyeon Ko, Christine Haewon Park, Byeongseok Jeong, Sang-Eun Lee, Hyeongseop Jeong, Sun-Hong Kim, Hyunwoo Park, Insuk So, Hyung Ho Lee","doi":"10.1038/s41594-024-01408-1","DOIUrl":"https://doi.org/10.1038/s41594-024-01408-1","url":null,"abstract":"Transient receptor potential (TRP) ion channels have a crucial role as cellular sensors, mediating diverse physical and chemical stimuli. The formation of heteromeric structures expands the functionality of TRP channels; however, their molecular architecture remains largely unknown. Here we present the cryo-electron microscopy structures of the human TRPC1/TRPC4 heteromer in the apo and antagonist-bound states, both consisting of one TRPC1 subunit and three TRPC4 subunits. The heteromer structure reveals a distinct ion-conduction pathway, including an asymmetrically constricted selectivity filter and an asymmetric lower gate, primarily attributed to the incorporation of TRPC1. Through a structure-guided electrophysiological assay, we show that both the selectivity filter and the lower part of the S6 helix participate in deciding overall preference for permeating monovalent cations. Moreover, we reveal that the introduction of one lysine residue of TRPC1 into the tetrameric central cavity is enough to render one of the most important functional consequences of TRPC heteromerization: reduced calcium permeability. Our results establish a framework for addressing the structure–function relationship of the heteromeric TRP channels.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"6 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142541576","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

DNA methylation shapes the Polycomb landscape during the exit from naive pluripotency DNA甲基化塑造了摆脱幼稚多能性过程中的多角体景观

Nature structural & molecular biology Pub Date : 2024-10-24 DOI: 10.1038/s41594-024-01405-4

Julien Richard Albert, Teresa Urli, Ana Monteagudo-Sánchez, Anna Le Breton, Amina Sultanova, Angélique David, Margherita Scarpa, Mathieu Schulz, Maxim V. C. Greenberg

{"title":"DNA methylation shapes the Polycomb landscape during the exit from naive pluripotency","authors":"Julien Richard Albert, Teresa Urli, Ana Monteagudo-Sánchez, Anna Le Breton, Amina Sultanova, Angélique David, Margherita Scarpa, Mathieu Schulz, Maxim V. C. Greenberg","doi":"10.1038/s41594-024-01405-4","DOIUrl":"https://doi.org/10.1038/s41594-024-01405-4","url":null,"abstract":"In mammals, 5-methylcytosine (5mC) and Polycomb repressive complex 2 (PRC2)-deposited histone 3 lysine 27 trimethylation (H3K27me3) are generally mutually exclusive at CpG-rich regions. As mouse embryonic stem cells exit the naive pluripotent state, there is massive gain of 5mC concomitantly with restriction of broad H3K27me3 to 5mC-free, CpG-rich regions. To formally assess how 5mC shapes the H3K27me3 landscape, we profiled the epigenome of naive and differentiated cells in the presence and absence of the DNA methylation machinery. Surprisingly, we found that 5mC accumulation is not required to restrict most H3K27me3 domains. Instead, this 5mC-independent H3K27me3 restriction is mediated by aberrant expression of the PRC2 antagonist Ezhip (encoding EZH inhibitory protein). At the subset of regions where 5mC appears to genuinely supplant H3K27me3, we identified 163 candidate genes that appeared to require 5mC deposition and/or H3K27me3 depletion for their activation in differentiated cells. Using site-directed epigenome editing to directly modulate 5mC levels, we demonstrated that 5mC deposition is sufficient to antagonize H3K27me3 deposition and confer gene activation at individual candidates. Altogether, we systematically measured the antagonistic interplay between 5mC and H3K27me3 in a system that recapitulates early embryonic dynamics. Our results suggest that H3K27me3 restraint depends on 5mC, both directly and indirectly. Our study also implies a noncanonical role of 5mC in gene activation, which may be important not only for normal development but also for cancer progression, as oncogenic cells frequently exhibit dynamic replacement of 5mC for H3K27me3 and vice versa.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"41 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489044","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Mechanism of actin filament severing and capping by gelsolin 凝胶球蛋白切断和覆盖肌动蛋白丝的机制

Nature structural & molecular biology Pub Date : 2024-10-24 DOI: 10.1038/s41594-024-01412-5

Kyle R. Barrie, Grzegorz Rebowski, Roberto Dominguez

引用次数: 0

Mechanism of polyadenylation-independent RNA polymerase II termination 不依赖多聚腺苷酸的 RNA 聚合酶 II 终止机制

Nature structural & molecular biology Pub Date : 2024-10-18 DOI: 10.1038/s41594-024-01409-0

Srinivasan Rengachari, Thomas Hainthaler, Christiane Oberthuer, Michael Lidschreiber, Patrick Cramer

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Time-course remodeling and pathology intervention of α-synuclein amyloid fibril by heparin and heparin-like oligosaccharides 肝素和肝素样寡糖对α-突触核蛋白淀粉样纤维的时程重塑和病理干预

Nature structural & molecular biology Pub Date : 2024-10-17 DOI: 10.1038/s41594-024-01407-2

Youqi Tao, Peng Xu, Shenqing Zhang, Wei Shangguan, Guang Yang, Kaien Liu, Xiang Li, Yunpeng Sun, Qinyue Zhao, Dan Li, Biao Yu, Cong Liu

{"title":"Time-course remodeling and pathology intervention of α-synuclein amyloid fibril by heparin and heparin-like oligosaccharides","authors":"Youqi Tao, Peng Xu, Shenqing Zhang, Wei Shangguan, Guang Yang, Kaien Liu, Xiang Li, Yunpeng Sun, Qinyue Zhao, Dan Li, Biao Yu, Cong Liu","doi":"10.1038/s41594-024-01407-2","DOIUrl":"https://doi.org/10.1038/s41594-024-01407-2","url":null,"abstract":"Amyloid fibrils represent a pathological state of protein polymer that is closely associated with various neurodegenerative diseases. Polysaccharides have a prominent role in recognizing amyloid fibrils and mediating their pathogenicity. However, the mechanism underlying the amyloid–polysaccharide interaction remains elusive. We also do not know its impact on the structure and pathology of formed fibrils. Here, we used cryo-electron microscopy to analyze the atomic structures of mature α-synuclein (α-syn) fibrils upon binding with polymeric heparin and heparin-like oligosaccharides. The fibril structure, including the helical twist and conformation of α-syn, changed over time upon the binding of heparin but not oligosaccharides. The sulfation pattern and numbers of saccharide units are important for the binding. Similarly, negatively charged biopolymers typically interact with amyloid fibrils, including tau and various α-syn polymorphs, leading to alterations in their conformation. Moreover, we show that heparin-like oligosaccharides can not only block neuronal uptake and propagation of formed α-syn fibrils but also inhibit α-syn fibrillation. This work demonstrates a distinctive activity of heparin and biopolymers in remodeling amyloid fibrils and suggests the pharmaceutical potential of heparin-like oligosaccharides.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"113 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142444002","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Structural basis for Vipp1 membrane binding: from loose coats and carpets to ring and rod assemblies Vipp1 膜结合的结构基础：从松散的外套和地毯到环状和杆状组件

Nature structural & molecular biology Pub Date : 2024-10-08 DOI: 10.1038/s41594-024-01399-z

Benedikt Junglas, David Kartte, Mirka Kutzner, Nadja Hellmann, Ilona Ritter, Dirk Schneider, Carsten Sachse

{"title":"Structural basis for Vipp1 membrane binding: from loose coats and carpets to ring and rod assemblies","authors":"Benedikt Junglas, David Kartte, Mirka Kutzner, Nadja Hellmann, Ilona Ritter, Dirk Schneider, Carsten Sachse","doi":"10.1038/s41594-024-01399-z","DOIUrl":"https://doi.org/10.1038/s41594-024-01399-z","url":null,"abstract":"Vesicle-inducing protein in plastids 1 (Vipp1) is critical for thylakoid membrane biogenesis and maintenance. Although Vipp1 has recently been identified as a member of the endosomal sorting complexes required for transport III superfamily, it is still unknown how Vipp1 remodels membranes. Here, we present cryo-electron microscopy structures of Synechocystis Vipp1 interacting with membranes: seven structures of helical and stacked-ring assemblies at 5–7-Å resolution engulfing membranes and three carpet structures covering lipid vesicles at ~20-Å resolution using subtomogram averaging. By analyzing ten structures of N-terminally truncated Vipp1, we show that helix α0 is essential for membrane tubulation and forms the membrane-anchoring domain of Vipp1. Lastly, using a conformation-restrained Vipp1 mutant, we reduced the structural plasticity of Vipp1 and determined two structures of Vipp1 at 3.0-Å resolution, resolving the molecular details of membrane-anchoring and intersubunit contacts of helix α0. Our data reveal membrane curvature-dependent structural transitions from carpets to rings and rods, some of which are capable of inducing and/or stabilizing high local membrane curvature triggering membrane fusion.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"5 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142384214","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0